Abstract The objective of this proposal is to use redox amplified radionuclide deposition to enable the non-invasive imaging of pancreatic beta-cells in type 1 diabetic patients using positron emission tomography (PET). It is becoming increasingly clear that diabetes is an epidemic and may be one of the 21st century's greatest health concerns. Molecular imaging tools are needed to monitor the progression of disease, the effectiveness of novel therapeutics, and to track the viability of transplanted cells. However, despite this need, the development of a whole-body molecular imaging technique to monitor beta-cells has remained elusive primarily due to inadequate signal-to-background, which prevents the resolution of target rare beta-cells (~1-2% of tissue) against background pancreatic cells. Here we propose an innovative solution, the amplification of PET imaging signals through enzyme catalyzed radionuclide reporter deposition. If successful, this method would represent a fundamentally new approach to signal amplification in radionuclide imaging. Such methods could dramatically increase signal output from beta-cell specific reporters while simultaneously suppressing background. A fundamental analysis of the problem suggests that such novel solutions are a requirement if we hope to detect rare cells using PET imaging. The development of generic methods to amplify PET signals could lead to valuable imaging tools for monitoring beta-cell mass and have an enormous impact on the clinical diagnosis, treatment, and understanding of type 1 diabetes.